Delving into the Latest Updates on HC-067047 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

HC-067047

Target

TRPV4

Action

antagonists

Mechanism

TRPV4 antagonists(Transient receptor potential cation channel subfamily V member 4 antagonists)

Therapeutic Areas

Urogenital Diseases

Active Indication-

Inactive Indication

Urinary Bladder Diseases

Originator Organization

The University of Texas at Austin

Active Organization-

Inactive Organization

The University of Texas at Austin

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC26H28F3N3O2

InChIKeyNCZYSQOTAYFTNM-UHFFFAOYSA-N

CAS Registry883031-03-6

Sepsis is a life-threatening condition characterized by multiple organ dysfunction syndrome resulted from dysregulated host responses to infection. Sepsis-associated encephalopathy (SAE) is one of the most common symptoms of acute-phase sepsis, with nearly 70 % of patients with sepsis ultimately developing SAE. Pyroptosis represents a type of cell death that is initiated by inflammation. This cell death type is associated with various infectious and noninfectious diseases. The gasdermin family proteins are crucial cell death executors and critical components in regulating the canonical pyroptosis pathway in microglia. In this review, we summarize the inhibitory effects of several drugs and genes on the pyroptosis pathway. Our findings suggest that several drugs (puerarin, VX765, HC067047, dexpramipexole, and Danhong injection), erbin gene, and TRIM45 knockdown improve SAE by suppressing the canonical pathway of NLRP3/caspase-1/gasdermin D-mediated pyroptosis. Therefore, they have significant importance in terms of brain protection. Moreover, we review the relevant literature published in recent years and summarize the research status and development prospects in this field to provide a basis for subsequent related research.

01 Apr 2025·Journal of Traditional Chinese Medicine

Electroacupuncture improves cyclophosphamide-induced bladder overactivity by reducing mechanotransduction in the rat urothelium.

Article

Author: Yuelai, Chen ; Ge, X U ; Wen, L I ; Jiwei, Feng ; Lumin, Liu ; Jiandang, Liu ; Xu, L I ; Junwei, H U

OBJECTIVE:

To investigate whether electroacupuncture (EA) therapy for overactive bladder (OAB) exerts its effect by modulating mechanosensitive channels in the urothelium, thereby improving bladder sensory function.

METHODS:

In this study, a rat model of OAB was created by using intraperitoneal injections of cyclophosphamide. We performed either EA or bladder perfusion with HC-067047 [a transient receptor potential vanilloid 4 (TRPV4) antagonist] and assessed the efficacy of electro-acupuncture in the treatment of OAB in rats viaurodynamic determination and Void spot assay. tissue morphology, distribution and expression of the TRPV4 protein and the amount of adenosine triphosphate (ATP) and Ca2+ released from urothelial cells in each group of rats were observed to identify the mechanism by which electroacupuncture improves OAB in rats.

RESULTS:

EA ameliorated bladder function and voiding behaviour, improved bladder uroepithelial tissue morphology, and significantly reduced the immun-ofluorescence intensity and the mRNA and protein expression levels of TRPV4 in the uroepithelium of OAB rats. Moreover, the simulated mechanical stimulation-induced increases in Ca²⁺ concentration and the release of ATP and acetylcholine (Ach) from bladder urothelial cells were inhibited. The changes in EA followed the same trend as those in HC-067047.

CONCLUSIONS:

These results suggest that EA inhibits bladder sensory function by downregulating the expression of mechanically activated TRPV4 ion channels distributed in bladder urothelial cells, which correspondingly decreases the inward flow of extracellular Ca²⁺ and reduces the release of ATP and Ach, thereby attenuating excitatory signals.

01 Apr 2025·CELLULAR ONCOLOGY

TRPV4 drives the progression of leiomyosarcoma by promoting ECM1 generation and co-activating the FAK/PI3K/AKT/GSK3β pathway

Article

Author: You, Yang ; Zhang, Chenlu ; Qian, Jiali ; Lu, Lili ; Luo, Rongkui ; Zhao, Yingying ; Huang, Chuxin ; Lu, Weiqi ; Cui, Jiefeng ; Xiao, Shuxiu ; Wang, Zhiming ; Zhang, Yong ; Tong, Hanxing ; Guo, Xi ; Hou, Yingyong ; Li, Wei ; Zhou, Yuhong ; Song, Zhengqing ; Zhou, Qiwen

PURPOSE:

Leiomyosarcoma (LMS) is an aggressive mesenchymal malignant tumor with poor therapeutic options, but the molecular mechanisms underlying LMS remain largely unknown. Increasing evidence indicates that transient receptor potential vanilloid 4 (TRPV4) levels are closely related to the advancement of various malignant tumors through diverse molecular mechanisms. However, the roles and regulatory mechanisms of TRPV4 in LMS progression remain unclear.

METHODS:

Immunohistochemistry, Western blot, and immunofluorescence were used to investigate the relationship between TRPV4 expression and LMS. Survival analysis was conducted to evaluate the association between TRPV4 levels and prognosis in LMS patients. Intracellular Ca²⁺ measurement, colony formation, CCK-8, wound healing and Transwell assays and peritoneal metastasis mouse model were used to verify the effect of TRPV4 activity and expression on LMS proliferation and metastasis. RNA-seq and proteomics were performed to explore the underlying mechanism.

RESULTS:

TRPV4 was upregulated in LMS tissues and cells and served as a novel prognostic factor. Moreover, TRPV4 overexpression enhanced cell proliferation, cell migration and invasion of LMS cells in vitro, as well as promoted tumor metastasis in vivo, which could be blocked by HC067047 intervention or TRPV4 knockdown. Combined RNA-seq and proteomics analysis of KEGG pathway indicated that ECM receptor interaction was obviously activated. Extracellular matrix protein 1 (ECM1) was identified as downstream gene of TRPV4. Mechanistically, TRPV4 overexpression increased ECM1 level and activated the FAK/PI3K/AKT/GSK3β pathway, which could be reversed by TRPV4 knockdown or LY294002 treatment. Moreover, ECM1 overexpression enhanced the activation of FAK/PI3K/AKT/GSK3β pathway. And simultaneous overexpression of TRPV4 and ECM1 synergistically activated this pathway.

CONCLUSION:

Our findings provide a novel mechanism by which TRPV4 directly activates Ca²⁺/FAK/PI3K/AKT/GSK3β pathway and further indirectly enhances the FAK/PI3K/AKT/GSK3β pathway through the promotion and secretion of ECM1 to promote LMS malignant progression. Targeting the TRPV4/FAK axis might be a promising potential strategy for prognosis and treatment of LMS.

100 Deals associated with HC-067047

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